Phosphoinositide 3-kinases (PI3-Ks) catalyze the synthesis of the phosphatidylinositol (PI) second messengers PI(3)P, PI(3,4)P2, and PI(3,4,5)P3 (PIP3) (Fruman et al., 1998). In the appropriate cellular context, these three lipids control diverse physiological processes including cell growth, survival, differentiation and chemotaxis (Katso et al., 2001). The PI3-K family comprises 15 kinases with distinct substrate specificities, expression patterns, and modes of regulation (Katso et al., 2001). The class I PI3-Ks (p110α, p110β, p110δ, and p110γ) are activated by tyrosine kinases or G-protein coupled receptors to generate PIP3, which engages downstream effectors such as the Akt/PDK1 pathway, the Tec family kinases, and the Rho family GTPases. The class II and III PI3-Ks play a key role in intracellular trafficking through the synthesis of PI(3)P and PI(3,4)P2. The PIKKs are protein kinases that control cell growth (mTORC1) or monitor genomic integrity (ATM, ATR, DNA-PK, and hSmg-1).
The importance of these enzymes in diverse pathophysiology has made the PI3-K family the focus of intense interest as a new class of drug targets (Ward et al., 2003). This interest has been fueled by the recent discovery that p110α is frequently mutated in primary tumors (Samuels et al., 2004) and evidence that the lipid phosphatase PTEN, an inhibitor of PI3-K signaling, is a commonly inactivated tumor suppressor (Cantley and Neel, 1999). Efforts are underway to develop small molecule PI3-K inhibitors for the treatment of inflammation and autoimmune disease (p110δ, p110γ, and mTOR), thrombosis (p110β, viral infection (the PIKKs) and cancer (p110α, mTOR, and others). Recently, the first selective inhibitors of these enzymes have been reported (Camps et al., 2005; Condliffe et al., 2005; Jackson et al., 2005; Knight et al., 2004; Lau et al., 2005; Sadhu et al., 2003).
The present invention meets these and other needs in the art by providing a new class of PI3-Kinase antagonists.